Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Drugs used in chemotherapy, such as docetaxel, doxorubicin , cyclophosphamide, paclitaxel, and gemcitabine work in different ways to stop tumor cells from dividing so they stop growing or die. Giving combination chemotherapy after surgery may kill any remaining tumor cells.

PURPOSE: This randomized phase III trial is studying three different combination chemotherapy regimens and comparing how well they work in treating women who have undergone surgery for node-positive breast cancer.

Further Study Information

OBJECTIVES:

Primary

• Compare disease-free survival in women with node-positive breast cancer treated with 3 different adjuvant chemotherapy regimens comprising dose-dense doxorubicin, cyclophosphamide, paclitaxel, and gemcitabine vs docetaxel, doxorubicin, and cyclophosphamide vs dose-dense doxorubicin, cyclophosphamide, and paclitaxel.

Secondary

• Compare overall survival, recurrence-free interval, and distant recurrence-free interval, in patients treated with these regimens.

• Compare the toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of positive lymph nodes (1-3 vs 4-9 vs ≥ 10), hormone receptor status (estrogen receptor [ER]- and progesterone receptor [PgR]- negative vs ER- and/or PgR-positive), type of prior surgery and planned radiotherapy (lumpectomy and local radiotherapy [RT] without regional RT vs lumpectomy and local RT with regional RT vs mastectomy without RT vs mastectomy with local or regional RT). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive doxorubicin IV over 15 minutes, cyclophosphamide IV over 30 minutes, and docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for 6 courses.

• Arm II: Patients receive AC chemotherapy comprising doxorubicin IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 14 days for 4 courses. Beginning 14 days after the last dose of AC, patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 14 days for 4 courses.

• Arm III: Patients receive AC chemotherapy as in arm II. Beginning 14 days after the last dose of AC, patients receive paclitaxel as in arm II and gemcitabine IV over 30-60 minutes on day 1. Treatment repeats every 14 days for 4 courses.

In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Beginning 3-12 weeks after the last dose of chemotherapy, patients with ER-positive and/or PgR-positive tumors receive hormonal therapy.

Beginning no sooner than 3 weeks after the last dose of chemotherapy, patients treated with lumpectomy undergo whole-breast radiotherapy. Patients treated with mastectomy may undergo chest wall and/or regional nodal radiotherapy.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 4,800 patients will be accrued for this study within 4 years.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive breast cancer, meeting all of the following staging criteria:

• Primary tumor T1-3 by clinical and pathological evaluation

• Ipsilateral lymph nodes cN0, cN1, or cN2a by clinical evaluation

• Ipsilateral lymph nodes pN1 (pN1mi, pN1a, pN1b, or pN1c), pN2a, pN3a, or pN3b* by pathologic evaluation

• Must have completed 1 of the following procedures for evaluation of pathological nodal status:

• Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes

• Sentinel lymphadenectomy alone allowed provided 1 of the following criteria is met:

• Pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1b

• No additional non-sentinel lymph nodes are removed

• Axillary lymphadenectomy without sentinel lymph node isolation procedure NOTE: *Only if due to microscopic involvement of internal mammary node detected by sentinel lymph node dissection AND has > 3 positive axillary lymph nodes

• Must have undergone prior lumpectomy or total mastectomy

• Lumpectomy patients:

• Surgical margins must be histologically free of invasive tumor AND ductal carcinoma in situ (DCIS) (lobular carcinoma in situ [LCIS] allowed)

• Additional operative procedures may be performed to obtain clear margins* even if axillary evaluation has been completed

• No diffuse tumors* by mammography

• No other clinically dominant mass or mammographically suspicious abnormality within the ipsilateral breast unless proven to be histologically benign OR if malignant, surgically removed with clear margins

• Planned whole breast irradiation required NOTE: *Patients with persistent positive margins or diffuse tumors must undergo total mastectomy to be eligible for this study

• No more than 84 days since last surgery for breast cancer staging or treatment

• No clinical or radiologic evidence of metastatic disease

• No contralateral breast cancer (invasive breast cancer or DCIS)

• No mass or mammographic abnormality in the opposite breast suspicious for malignancy unless there is biopsy evidence that the mass is not malignant

• No suspicious nodes in the contralateral axilla or suspicious supraclavicular nodes unless there is biopsy evidence of no tumor involvement

• No prior breast cancer, including DCIS

• LCIS allowed

• Hormone receptor status:

• Estrogen receptor (ER) status known

• Progesterone receptor status known only if ER-negative

PATIENT CHARACTERISTICS:

Age

• Not specified

Sex

• Female

Menopausal status

• Not specified

Performance status

• Zubrod 0-1

Life expectancy

• At least 10 years

Hematopoietic

• Absolute granulocyte count ≥ 1,200/mm^3

• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ upper limit of normal (ULN)* (1.5 times ULN if due to Gilbert's disease or similar syndrome)

• Alkaline phosphatase ≤ 2.5 times ULN*

• AST ≤ 1.5 times ULN*

• No hepatic disease that would preclude study participation NOTE: *Bilirubin, AST, OR alkaline phosphatase > ULN allowed provided no metastatic liver disease is present on imaging

Renal

• Postoperative creatinine ≤ ULN

• No renal disease that would preclude study participation

Cardiovascular

• LVEF ≥ lower limit of normal by echocardiogram or MUGA

• No cardiac disease that would preclude the use of anthracyclines, including any of the following:

• History of myocardial infarction documented by elevated cardiac enzymes or regional wall abnormalities

• Angina pectoris requiring anti-anginal medication

• Documented history of congestive heart failure

• Serious cardiac arrhythmia requiring medication

• Severe conduction abnormality

• Valvular disease with documented cardiac function compromise

• Uncontrolled hypertension, defined as blood pressure > 160/100 mm Hg with antihypertensive therapy

• No other cardiovascular disease that would preclude study participation

Other

• Not pregnant or nursing

• Fertile patients must use effective non-hormonal contraception

• No other malignancy within the past 5 years except treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, melanoma in situ, or carcinoma in situ of the colon

• Considered to be low-risk for recurrence

• No condition that would preclude corticosteroid administration

• No sensory or motor neuropathy ≥ grade 2

• No other nonmalignant systemic disease that would preclude study participation

• No psychiatric or addictive disorder or other condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy for current breast cancer

• No prior anthracycline or taxane therapy for any malignancy

Endocrine therapy

• See Disease Characteristics

• Prior hormonal therapy for breast cancer allowed provided the duration of therapy was ≤ 28 days and it was administered before study entry

• No concurrent sex hormonal therapy (e.g., birth control pills, ovarian hormone replacement therapy, or Femring®)

• Concurrent Vagifem® or Estring® for the management of vaginal or urinary symptoms allowed

• No concurrent raloxifene, tamoxifen, or other selective estrogen-receptor modulators (SERMs) for osteoporosis or breast cancer prevention

Radiotherapy

• See Disease Characteristics

• No prior radiotherapy for current breast cancer

• No concurrent partial breast irradiation (lumpectomy patients)

• Concurrent irradiation of regional lymph nodes allowed provided plans are declared prior to study entry

Surgery

• See Disease Characteristics

Other

• Concurrent calcium supplements, cholecalciferol (vitamin D), calcitonin (e.g., Miacalcin®), or bisphosphonates (e.g., Actonel® or Fosamax®) for the management of osteoporosis allowed

• No other concurrent investigational agents for the treatment of breast cancer

Trial Contact Information

Trial Lead Organizations/Sponsors

National Surgical Adjuvant Breast and Bowel Project

Sandra M. Swain

Study Chair

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00093795
Information obtained from ClinicalTrials.gov on December 14, 2011

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